Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Hart, Steven N.; Cui, Yue; Klaassen, Curtis D.; Zhong, Xiao Bo

doi:10.1124/dmd.108.023812

Cited by 93 publications

(93 citation statements)

References 29 publications

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“…The advantages of these models include rapid growth, easy maintenance, and the development of genetic manipulation techniques for mechanistic studies with gainof-function and loss-of-function strategies. Several laboratories, including ours, have examined the ontogenic gene expression profiles in mouse or rat livers for some phase-I genes, including P450s (Hart et al, 2009;Cui et al, 2012b), Ces (Zhu et al, 2009), aldo-keto reductase (Akr) (Pratt-Hyatt et al, 2013), Adh and aldehyde dehydrogenase (Aldh) (Smolen et al, 1990;Alnouti and Klaassen, 2008), Pon (Li et al, 1997), and Fmo (Falls et al, 1995;Cherrington et al, 1998;Janmohamed et al, 2004). The developmental expression patterns of some phase-I genes in mice and rats are similar to those in humans.…”

Section: Introductionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.

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Section: Introductionmentioning

confidence: 99%

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

et al. 2013

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“…Advantages of these models include rapid growth, easy maintenance, and the development of genetic manipulation techniques for mechanistic studies with gain-of-function and loss-of-function strategies. Several researchers have examined the ontogenic gene expression profiles of a few P450s in mouse or rat liver (Choudhary et al, 2004;Alcorn et al, 2007;Cherala et al, 2007;Hart et al, 2009;Li et al, 2009a). Developmental expression patterns of some P450s in mice and rats are similar to those in humans.…”

Section: Introductionmentioning

confidence: 99%

RNA Sequencing Reveals Dynamic Changes of mRNA Abundance of Cytochromes P450 and Their Alternative Transcripts during Mouse Liver Development

Peng¹,

Yoo²,

Gunewardena³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Cytochromes P450 (P450s) are a superfamily of enzymes that have critical functions in liver to catalyze the biotransformation of numerous drugs. However, the functions of most P450s are not mature at birth, which can markedly affect the metabolism of drugs in newborns. Therefore, characterization of the developmental profiles and regulatory mechanisms of P450 expression is needed for more rational drug therapy of pediatric patients. An animal model is indispensable for studying the mechanisms of postnatal development of the P450s. Hence we used RNA sequencing (RNA-Seq) to provide a "true quantification" of mRNA expression of all P450s in mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used. Total mRNAs of the 103 mouse P450s displayed two rapid increasing stages after birth, reflecting critical functional transition of liver during development. Four ontogenic expression patterns were identified among the 71 significantly expressed P450s, which categorized genes into neonatal-, adolescent-, adolescent/adult-, and adult-enriched groups. The 10 most highly expressed subfamilies of mouse P450s in livers of adult mice were CYP2E, -2C, -2D, -3A, -4A, -2F, -2A, -1A, -4F, and -2B, which showed diverse expression profiles during development. The expression patterns of multiple members within a P450 subfamily were often classified to different groups. RNA-Seq also enabled the quantification of known transcript variants of CYP2C44, CYP2C50, CYP2D22, CYP3A25, and CYP26B1 and identification of novel transcripts for CYP2B10, CYP2D26, and CYP3A13. In conclusion, this study reveals the mRNA abundance of all the P450s in mouse liver during development and provides a foundation for mechanistic studies in the future.

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“…This process occurs within the first 30 days in rodents but takes up to 5 years in humans (16). During this postnatal development, the liver acquires an adult gene expression program, and expression of several drug-metabolizing enzymes, transporters, and other enzymes involved in major metabolic processes is initiated (7,10). Another striking feature of postnatal liver development is the increase in liver size due to extensive hepatic cell proliferation, which increases liver size to the adult liver weight-to-body weight ratio (1)(2)(3)12).…”

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confidence: 99%

Yes-associated protein is involved in proliferation and differentiation during postnatal liver development

Septer

Edwards²,

Gunewardena

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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It is known that the liver undergoes size increase and differentiation simultaneously during the postnatal period. Cells in the liver undergo a period of well-controlled proliferation to achieve the adult liver-to-body weight ratio. The postnatal liver growth is also accompanied by simultaneous hepatic differentiation. However, the mechanisms of liver size regulation and differentiation are not completely clear. Herein we report that yes-associated protein (Yap), the downstream effector of the Hippo Kinase signaling pathway, plays a role in liver size regulation and differentiation during the postnatal liver growth period. Postnatal liver growth was studied in C57BL/6 mice over a time course of postnatal days (PND) 0- 30. Analysis of nuclear Yap by Western blot indicated peak Yap activation between PND15–20, which coincided with increased cyclin D1 expression and liver cell proliferation. Analysis of postnatal liver development in Yap+/− mice revealed a significant decrease in the liver-to-body weight ratio compared with Yap+/+ mice at PND15 and -30. Yap+/− mice exhibited a significant decrease in postnatal liver cell proliferation, but no change in apoptosis was observed. Furthermore, global gene expression analysis of Yap+/− livers revealed a role of Yap in regulation of genes involved in bile acid metabolism, retinoic acid metabolism, ion transport, and extracellular matrix proteins. Taken together, these data indicate that Yap plays a role in both cell proliferation and possibly in hepatic differentiation during postnatal liver development.

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Three Patterns of Cytochrome P450 Gene Expression during Liver Maturation in Mice

Cited by 93 publications

References 29 publications

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

RNA Sequencing Reveals Dynamic Changes of mRNA Abundance of Cytochromes P450 and Their Alternative Transcripts during Mouse Liver Development

Yes-associated protein is involved in proliferation and differentiation during postnatal liver development

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